III III a IIOI OlD III OlD IIO III DID III 100 III0 II uii IIi

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1 III III a IIOI OlD III OlD IIO III DID III 100 III0 II uii IIi US oi ^^_._.,o.i ^,) United States (12) Patent Application Publication Buyse et al. (43) Pub. Date: Oct. 28, (54) HPV POLYEPITOPE CONSTRUCTS AND USES THEREOF (76) Inventors: Marie-Ange Buyse, Merelbeke (BE); Denise Baker, Poway, CA (US) Correspondence Address: NIXON & VANDERHYE, PC 901 NORTH GLEBE ROAD, 11TH FLOOR ARLINGTON, VA (US) (21) Appl. No.: 12/451,743 (22) PCT Filed: May 29, 2008 Related U.S. Application Data (60) Provisional application No. 60/924,778, filed on May 31, (30) Foreign Application Priority Data Jun. 12, 2007 (EP) (51) Int. Cl. A61K 39/12 C07K 7/06 C07H 21/04 C12N 15/63 C12N 5/10 A61P 31/12 (52) U.S. Cl... Publication Classification ( ) ( ) ( ) ( ) ( ) ( ) 424/204.1; 530/328; 536/23.1; 435/320.1; 435/325 (86) PCT No.: PCT/EP2008/ (57) ABSTRACT The present invention is directed to HPV polyepitope con- 371 (c)(1), struct and the use thereoffor the prevention and/or treatment (2), (4) Date Jul. 1, 2010 of HPV infection.

2 Patent Application Publication Oct. 28, 2010 Sheet 1 of 17 US 2010/ Al A. ATCVSHRGLY - STDLRDHIDY - ATMCRHYKR - ILYAHIQCL - GTLGIVCPV - CYSLYGTTF - DSVYGDTLER - QVVPAYNISK - LYNLLIRCF - FVYIPLFLI - YYMTDAGTW - VVLLLVRYK - ISDYRHYCY - TVSATQLVK - STAAALYWYK - FVVYRDSIPK - SYFGMSFIHF - YMLDLQPETV - VYDFAFRDLCI - LQDKIIDHY - TLHDIILECV - KLTNTGLYNV - SVICFVNSK - MYVCCHVPL - SLQDIEITCV - CLYLHIQSL - AATKYPLLK - VYVFCFLLPM - KQGAMLAVFK - LSQMVQWAY - PYAVCDKCF - TVYVFCFLL - ATLQDIVLH - KSLFGMSLMK - GTGCNGWFY - RFHNIRGRF - KLLSK LLCV - STVSVGTAK - VAWDSVYYM - GYNTFYIEF - LYGVSFSEL - QVDYYGLYY - KSAIVTLTY - TLEKLTNTGLY B. GLYYVHEGIRTYFVQ - FLNTVAIPDSVQILV - QRFHNIRGRWTGRCM - TNTGLYNLLIRCLRCQ - IEFITFLGALKSFLK - PEWIQRQTVLQHSFN - LFVVYRDSIPHAACHK - IRTLEDLLMGTLGIV - LDLQPETTDLYCYEQ - LQAIEL QLTLETIYN - FQQLFLNTLSFVCPW - WKHMRLECAIYYKAR - LCTELQTTIHDIILE - FKTLIQPFILYAHIQ - LYWYKTGISNISEVY - EVFEFAFKDLFVVYR - HKAIELQMALQGLAQ - AKFVAAWTLKAAA FIGURE 1

3 Patent Application Publication Oct. 28, 2010 Sheet 2 of 17 US 2010/ Al A. FYSKVSEFRW RTEVYQFAFR VTTRYPLLR VFTFPNPFPF YTNWKFIYL - SVYGETLEK AVMCRHYKR VYGTTLEKL VVFIYIPLF KLLEKLLCI - GTGCNG WFY QTEPDTSNY PYLHSRLVVF LTDVSIACVY HYTNWKFIF FIYIPLFVI MVMLMLVRFK NTELYNLLI FLFTDLTIV FLLCFCVLL ATTPIIHLK - KLTNKG ICDL LQDKILDHY NTGILTVTY VMDDSEIAY STWHWTGCNK SYFGMSFIHF LSSALEIPY LSQMVQWAY SLVFLLCFSV TLYAHIQCL VFTFPHAFPF RQMNMSQWIK TLQEIVLHV AFTDLTIVY -ISFAGIVTK YVVWDSIYYI - YYITETG IW FYSRIRELRF VYQFAFKDL FLLCFSVCL YQFAFKDLCV SVYGTTLER KVSEFRWYRY ELDPVDLLCY STAAALYWYR VYVCAFAWLL B. EIVLHLEPQNELDPV IRILQELLMGSFGIV TGRCIACWRRPRTET WKHIRLECVLMYKAR LCIVYRDCIAYAACH PEWIERQTVLQHSFN PINISKSKAHKAIEL LRTLQQLFLSTLSFV FHSIAGQYRGQCNTC TTPIIHLKGDANILK DWVMAIFGVNPTVAEGF PRKLHELSSALEIPY FKTLIKPATLYAHIQ TIPNSVQISVGYMTI NGWFYVEAVIDRQTG VLDFAFTDLTIVYRD AKFVAAWTLKAAA FIGURE 2

4 Patent Application Publication Oct. 28, 2010 Sheet 3 of 17 US 2010/ Al AFTDLTIVY - STWHWTGCNK - KLLEKLLCI YQFAFKDLCV MVMLMLVRFK LQDKILDHY FLLCFCVLL SVYGTTLER VTTRYPLLR TLQEIVLHV YYITETGIW VVFIYIPLF QTEPDTSNY ELDPVDLLCY LTDVSIACVY RTEVYQFAFR PYLHSRLVVF ISFAGIVTK VMDDSEIAY FYSRIRELRF FIYIPLFVI VFTFPHAFPF FYSKVSEFRW SLVFLLCFSV STAAALYWYR TLYAHIQCL HYTNWKFIF NTELYNLLI SYFGMSFIHF KLTNKGICDL SVYGETLEK VYVCAFAWLL VYGTTLEKL LSQMVQWAY YVVWDSIYYI GTGCNGWFY AVMCRHYKR FLLCFSVCL VYQFAFKDL KVSEFRWYRY YTNWKFIYL LSSALEIPY FLFTDLTIV ATTPIIHLK RQMNMSQWIK NTGILTVTY VET FPNPFPF FIGURE 3

5 Patent Application Publication Oct. 28, 2010 Sheet 4 of 17 US 2010/ Al KSLFGMSLMK STDLRDHIDY LQDKIIDHY LYNLLIRCF AATKYPLLK QVDYYGLYY VVLLLVRYK STVSVGTAK KSAIVTLTY FVVYRDSIPK GTLGIVCPV STAAALYWYK ISDYRHYCY CLYLHIQSL FVYIPLFLI VYVFCFLLPM YYMTDAGTW SYFGMSFIHF LSQMVQWAY DSVYGDTLER SLQDIEITCV SVICFVNSK CYSLYGTTF VAWDSVYYM QVVPAYNISK GYNTFYIEF ATLQDIVLH TVYVFCFLL ILYAHIQCL TVSATQLVK TLHDIILECV PYAVCDKCF KLLSKLLCV KLTNTGLYNV MYVCCHVPL VYDFAFRDLI TLEKLTNTGLY GTGCNGWFY LYGVSFSEL KQGAMLAVFK - ATMCRHYKR - ATCVSHRGLY - RFHNIRGRF ;I YMLDLQPETV FIGURE 4

6 Patent Application Publication Oct. 28, 2010 Sheet 5 of 17 US 2010/ Al FIGURE 5 A. ICCG6137 Amino acid sequence MGMQVQIQSLFLLLLWVPGSRGAFTDLTIVYNSTWHWTGCNKKAAAKLLEKLLCINA YQFAFKDLCVKMVMLMLVRFKNAALQDKILDHYKAAFLLCFCVLLNSVYGTTLERNA AVTTRYPLLRNATLQEIVLHVNYYITETGIWKVVFIYIPLFNQTEPDTSNYGAAELD PVDLLCYKAAALTDVSIACVYNAARTEVYQFAFRNPYLHSRLVVFNISFAGIVTKKV MDDSEIAYNAFYSRIRELRFKAAAFIYIPLFVIKAVFTFPHAFPFNAFYSKVSEFRW KSLVFLLCFSVNASTAAALYWYRKATLYAHIQCLNAAHYTNWKFIFNAANTELYNLL INASYFGMSFIHFKLTNKGICDLNSVYGETLEKNVYVCAFAWLLNVYGTTLEKLKLS QMVQWAYKAAAYVVWDSIYYINGTGCNGWFYGAAAVMCRHYKRNFLLCFSVCLNAVY QFAFKDLKAAKVSEFRWYRYKYTNWKFIYLNAALSSALEIPYKAAFLFTDLTIVNAA TTPIIHLKNAAARQMNMSQWIKNTGILTVTYNVFTFPNPFPFKAAAEIVLHLEPQNE LDPVGPGPGIRILQELLMGSFGIVGPGPGTGRCIACWRRPRTETGPGPGWKHIRLEC VLMYKARGPGPGLCIVYRDCIAYAACHGPGPGPEWIERQTVLQHSFNGPGPGPINIS KSKAHKAIELGPGPGLRTLQQLFLSTLSFVGPGPGFHSIAGQYRGQCNTCGPGPGTT PIIHLKGDANILKGPGPGDWVMAIFGVNPTVAEGFGPGPGPRKLHELSSALEIPYGP GPGFKTLIKPATLYAHIQGPGPGTIPNSVQISVGYMTIGPGPGNGWFYVEAVIDRQT GGPGPGVLDFAFTDLTIVYRDGPGPGAKFVAAWTLKAAA (SEQ ID NO 123) B. ICCG6137 DNA sequence ATGGGCATGCAGGTGCAGATCCAGAGCCTGTTCCTGCTGCTGCTGTGGGTGCCCGGC AGCAGGGGCGCTTTCACCGACCTGACCATCGTGTACAACAGCACCTGGCACTGGACC GGCTGCAACAAGAAAGCCGCTGCCAAGCTGCTGGAAAAGCTGCTGTGCATCAACGCC TATCAGTTTGCCTTCAAGGACCTGTGCGTGAAGATGGTGATGCTGATGCTGGTGCGG TTCAAGAATGCCGCTCTCCAGGACAAGATCCTGGACCACTACAAGGCCGCCTTTCTG CTGTGCTTCTGCGTGCTGCTGAACAGCGTGTACGGCACCACCCTGGAACGGAACGCC GCCGTGACCACCAGATACCCCCTGCTGCGGAATGCCACCCTCCAGGAAATCGTCCTG CACGTCAATTACTACATCACCGAGACCGGCATCTGGAAGGTGGTGTTCATCTACATC CCCCTGTTCAACCAGACCGAGCCCGACACCAGCAACTACGGAGCCGCCGAACTCGAT CCCGTGGACCTGCTGTGCTACAAAGCCGCTGCCCTGACCGACGTGAGCATCGCCTGC GTGTACAACGCCGCCAGGACCGAGGTGTACCAGTTTGCCTTTCGGAACCCCTACCTG CACAGCAGACTGGTGGTGTTTAACATCAGCTTCGCCGGCATCGTGACCAAGAAAGTG ATGGACGACAGCGAGATCGCCTACAACGCCTTCTACAGCCGGATCAGAGAGCTGAGG TTCAAAGCCGCTGCCTTTATCTACATTCCTCTGTTCGTGATCAAGGCCGTGTTCACC TTCCCCCACGCCTTCCCTTTCAATGCCTTCTACTCCAAGGTGTCCGAGTTCCGGTGG AAGAGCCTGGTGTTCCTGCTGTGTTTCAGCGTGAACGCCAGCACCGCCGCTGCCCTG TACTGGTACAGGAAGGCCACCCTGTACGCCCATATCCAGTGCCTGAATGCCGCCCAC TACACCAACTGGAAGTTCATCTTCAATGCCGCCAACACCGAGCTGTACAACCTGCTG ATCAACGCCAGCTACTTCGGCATGAGCTTCATCCACTTCAAGCTGACCAACAAGGGC ATCTGCGACCTGAACTCCGTGTACGGCGAGACACTGGAAAAGAACGTGTACGTGTGC GCCTTCGCCTGGCTGCTGAACGTGTATGGCACAACACTGGAAAAACTGAAGCTGTCC CAGATGGTGCAGTGGGCCTATAAAGCCGCCGCCTACGTGGTGTGGGACAGCATCTAC TATATCAACGGCACCGGCTGTAACGGCTGGTTTTACGGCGCCGCTGCCGTGATGTGC CGGCACTACAAGCGGAATTTTCTGCTGTGTTTTTCCGTGTGCCTGAACGCCGTGTAT

7 Patent Application Publication Oct. 28, 2010 Sheet 6 of 17 US 2010/ Al CAGTTCGCCTTTAAGGATCTGAAGGCTGCCAAAGTGTCTGAGTTCAGATGGTACAGG TACAAGTACACAAATTGGAAGTTTATCTATCTGAACGCCGCCCTGAGCAGCGCCCTG GAAATCCCCTATAAGGCTGCCTTCCTGTTCACCGATCTGACTATTGTGAACGCCGCC ACCACCCCCATCATCCACCTGAAAAACGCCGCTGCCAGGCAGATGAACATGAGCCAG TGGATCAAGAACACCGGCATCCTGACCGTGACCTACAACGTGTTTACCTTTCCCAAC CCTTTCCCCTTTAAAGCCGCTGCCGAGATCGTGCTGCACCTGGAACCCCAGAACGAG CTGGACCCTGTGGGCCCTGGCCCTGGCATCAGAATCCTCCAGGAACTGCTGATGGGC AGCTTCGGCATCGTGGGCCCAGGCCCCGGAACCGGCCGGTGCATCGCCTGTTGGCGG AGGCCCCGGACCGAGACAGGCCCTGGACCCGGCTGGAAGCACATCCGGCTGGAATGC GTGCTGATGTACAAGGCCAGGGGACCCGGCCCTGGCCTCTGTATCGTGTACCGCGAC TGCATCGCCTACGCCGCCTGCCACGGCCCAGGACCTGGCCCCGAGTGGATCGAGCGG CAGACCGTGCTCCAGCATAGCTTCAACGGACCCGGACCAGGCCCCATCAACATCAGC AAGAGCAAGGCCCACAAGGCCATCGAGCTGGGCCCTGGGCCCGGACTGCGGACCCTC CAGCAGCTGTTCCTGAGCACCCTGAGCTTCGTGGGACCTGGGCCAGGCTTCCACAGC ATCGCCGGCCAGTACCGGGGCCAGTGCAACACCTGCGGCCCAGGGCCAGGCACCACA CCTATTATTCACCTGAAGGGCGACGCCAACATCCTGAAGGGGCCAGGACCCGGCGAC TGGGTGATGGCCATCTTCGGCGTGAACCCCACCGTGGCCGAGGGCTTCGGACCTGGA CCTGGGCCTAGGAAGCTGCACGAGCTGTCCTCTGCCCTGGAAATTCCTTACGGCCCT GGCCCAGGCTTCAAGACCCTGATCAAGCCCGCCACACTGTATGCCCACATTCAGGGC CCTGGACCAGGCACCATCCCCAACAGCGTGCAGATCAGCGTGGGCTACATGACCATC GGACCAGGGCCTGGCAATGGCTGGTTCTACGTGGAGGCCGTGATCGACAGGCAGACC GGCGGACCTGGCCCAGGGGTGCTGGACTTCGCCTTTACAGACCTGACAATTGTGTAC CGGGACGGCCCTGGGCCTGGCGCCAAGTTCGTGGCCGCCTGGACCCTGAAGGCCGCT GCCTGA (SEQ ID NO 124) C. AFTDLTIVYNSTWHWTGCNKKAAAKLLEKLLCINAYQFAFKDLCVKMVMLMLVRFKN AALQDKILDHYKAAFLLCFCVLLNSVYGTTLERNAAVTTRYPLLRNATLQEIVLHVN YYITETGIWKVVFIYIPLFNQTEPDTSNYGAAELDPVDLLCYKAAALTDVSIACVYN AARTEVYQFAFRNPYLHSRLVVFNISFAGIVTKKVMDDSEIAYNAFYSRIRELRFKA AAFIYIPLFVIKAVFTFPHAFPFNAFYSKVSEFRWKSLVFLLCFSVNASTAAALYWY RKATLYAHIQCLNAAHYTNWKFIFNAANTELYNLLINASYFGMSFIHFKLTNKGICD LNSVYGETLEKNVYVCAFAWLLNVYGTTLEKLKLSQMVQWAYKAAAYVVWDSIYYIN GTGCNGWFYGAAAVMCRHYKRNFLLCFSVCLNAVYQFAFKDLKAAKVSEFRWYRYKY TNWKFIYLNAALSSALEIPYKAAFLFTDLTIVNAATTPIIHLKNAAARQMNMSQWIK NTGILTVTYNVFTFPNPFPFKAAAEIVLHLEPQNELDPVGPGPGIRILQELLMGSFG IVGPGPGTGRCIACWRRPRTETGPGPGWKHIRLECVLMYKARGPGPGLCIVYRDCIA YAACHGPGPGPEWIERQTVLQHSFNGPGPGPINISKSKAHKAIELGPGPGLRTLQQL FLSTLSFVGPGPGFHSIAGQYRGQCNTCGPGPGTTPIIHLKGDANILKGPGPGDWVM AI FGVNPTVAEGFGPGPGPRKLHELSSALEIPYGPGPGFKTLIKPATLYAHIQGPGP GTIPNSVQISVGYMTIGPGPGNGWFYVEAVIDRQTGGPGPGVLDFAFTDLTIVYRDG PGPGAKFVAAWTLKAAA (SEQ ID NO 156) FIGURE 5 cont.1

8 Patent Application Publication Oct. 28, 2010 Sheet 7 of 17 US 2010/ Al a GCTTTCACCGACCTGACCATCGTGTACAACAGCACCTGGCACTGGACCGGCTGCAAC AAGAAAGCCGCTGCCAAGCTGCTGGAAAAGCTGCTGTGCATCAACGCCTATCAGTTT GCCTTCAAGGACCTGTGCGTGAAGATGGTGATGCTGATGCTGGTGCGGTTCAAGAAT GCCGCTCTCCAGGACAAGATCCTGGACCACTACAAGGCCGCCTTTCTGCTGTGCTTC TGCGTGCTGCTGAACAGCGTGTACGGCACCACCCTGGAACGGAACGCCGCCGTGACC ACCAGATACCCCCTGCTGCGGAATGCCACCCTCCAGGAAATCGTCCTGCACGTCAAT TACTACATCACCGAGACCGGCATCTGGAAGGTGGTGTTCATCTACATCCCCCTGTTC AACCAGACCGAGCCCGACACCAGCAACTACGGAGCCGCCGAACTCGATCCCGTGGAC CTGCTGTGCTACAAAGCCGCTGCCCTGACCGACGTGAGCATCGCCTGCGTGTACAAC GCCGCCAGGACCGAGGTGTACCAGTTTGCCTTTCGGAACCCCTACCTGCACAGCAGA CTGGTGGTGTTTAACATCAGCTTCGCCGGCATCGTGACCAAGAAAGTGATGGACGAC AGCGAGATCGCCTACAACGCCTTCTACAGCCGGATCAGAGAGCTGAGGTTCAAAGCC GCTGCCTTTATCTACATTCCTCTGTTCGTGATCAAGGCCGTGTTCACCTTCCCCCAC GCCTTCCCTTTCAATGCCTTCTACTCCAAGGTGTCCGAGTTCCGGTGGAAGAGCCTG GTGTTCCTGCTGTGTTTCAGCGTGAACGCCAGCACCGCCGCTGCCCTGTACTGGTAC AGGAAGGCCACCCTGTACGCCCATATCCAGTGCCTGAATGCCGCCCACTACACCAAC TGGAAGTTCATCTTCAATGCCGCCAACACCGAGCTGTACAACCTGCTGATCAACGCC AGCTACTTCGGCATGAGCTTCATCCACTTCAAGCTGACCAACAAGGGCATCTGCGAC CTGAACTCCGTGTACGGCGAGACACTGGAAAAGAACGTGTACGTGTGCGCCTTCGCC TGGCTGCTGAACGTGTATGGCACAACACTGGAAAAACTGAAGCTGTCCCAGATGGTG CAGTGGGCCTATAAAGCCGCCGCCTACGTGGTGTGGGACAGCATCTACTATATCAAC GGCACCGGCTGTAACGGCTGGTTTTACGGCGCCGCTGCCGTGATGTGCCGGCACTAC AAGCGGAATTTTCTGCTGTGTTTTTCCGTGTGCCTGAACGCCGTGTATCAGTTCGCC TTTAAGGATCTGAAGGCTGCCAAAGTGTCTGAGTTCAGATGGTACAGGTACAAGTAC ACAAATTGGAAGTTTATCTATCTGAACGCCGCCCTGAGCAGCGCCCTGGAAATCCCC TATAAGGCTGCCTTCCTGTTCACCGATCTGACTATTGTGAACGCCGCCACCACCCCC ATCATCCACCTGAAAAACGCCGCTGCCAGGCAGATGAACATGAGCCAGTGGATCAAG AACACCGGCATCCTGACCGTGACCTACAACGTGTTTACCTTTCCCAACCCTTTCCCC TTTAAAGCCGCTGCCGAGATCGTGCTGCACCTGGAACCCCAGAACGAGCTGGACCCT GTGGGCCCTGGCCCTGGCATCAGAATCCTCCAGGAACTGCTGATGGGCAGCTTCGGC ATCGTGGGCCCAGGCCCCGGAACCGGCCGGTGCATCGCCTGTTGGCGGAGGCCCCGG ACCGAGACAGGCCCTGGACCCGGCTGGAAGCACATCCGGCTGGAATGCGTGCTGATG TACAAGGCCAGGGGACCCGGCCCTGGCCTCTGTATCGTGTACCGCGACTGCATCGCC TACGCCGCCTGCCACGGCCCAGGACCTGGCCCCGAGTGGATCGAGCGGCAGACCGTG CTCCAGCATAGCTTCAACGGACCCGGACCAGGCCCCATCAACATCAGCAAGAGCAAG GCCCACAAGGCCATCGAGCTGGGCCCTGGGCCCGGACTGCGGACCCTCCAGCAGCTG TTCCTGAGCACCCTGAGCTTCGTGGGACCTGGGCCAGGCTTCCACAGCATCGCCGGC CAGTACCGGGGCCAGTGCAACACCTGCGGCCCAGGGCCAGGCACCACACCTATTATT CACCTGAAGGGCGACGCCAACATCCTGAAGGGGCCAGGACCCGGCGACTGGGTGATG GCCATCTTCGGCGTGAACCCCACCGTGGCCGAGGGCTTCGGACCTGGACCTGGGCCT AGGAAGCTGCACGAGCTGTCCTCTGCCCTGGAAATTCCTTACGGCCCTGGCCCAGGC TTCAAGACCCTGATCAAGCCCGCCACACTGTATGCCCACATTCAGGGCCCTGGACCA GGCACCATCCCCAACAGCGTGCAGATCAGCGTGGGCTACATGACCATCGGACCAGGG CCTGGCAATGGCTGGTTCTACGTGGAGGCCGTGATCGACAGGCAGACCGGCGGACCT GGCCCAGGGGTGCTGGACTTCGCCTTTACAGACCTGACAATTGTGTACCGGGACGGC CCTGGGCCTGGCGCCAAGTTCGTGGCCGCCTGGACCCTGAAGGCCGCTGCC (SEQ ID NO 157) FIGURE 5 cont

9 Patent Application Publication Oct. 28, 2010 Sheet 8 of 17 US 2010/ Al FIGURE 6 A. ICCG6138 Amino acid sequence MGMQVQIQSLFLLLLWVPGSRGFYSKVSEFRWKAARTEVYQFAFRNAAVTTRYPLLR NVFTFPNPFPFNYTNWKFIYLNASVYGETLEKGAAVMCRHYKRNAVYGTTLEKLKVV FIYIPLFGAAKLLEKLLCINGTGCNGWFYNQTEPDTSNYNAAAPYLHSRLVVFGAAA LTDVSIACVYNAHYTNWKFIFGAAFIYIPLFVIKAAAMVMLMLVRFKNAANTELYNL LINFLFTDLTIVNFLLCFCVLLNAATTPIIHLKGAAKLTNKGICDLNALQDKILDHY KNTGILTVTYGAAAVMDDSEIAYNSTWHWTGCNKKAASYFGMSFIHFKLSSALEIPY KLSQMVQWAYNSLVFLLCFSVNATLYAHIQCLNVFTFPHAFPFNAAARQMNMSQWIK NATLQEIVLHVNAAFTDLTIVYNISFAGIVTKKYVVWDSIYYINYYITETGIWKAAA FYSRIRELRFKVYQFAFKDLKAFLLCFSVCLNAAYQFAFKDLCVKSVYGTTLERNKV SEFRWYRYKAAELDPVDLLCYKSTAAALYWYRKAAAVYVCAFAWLLEIVLHLEPQNE LDPVGPGPGIRILQELLMGSFGIVGPGPGTGRCIACWRRPRTETGPGPGWKHIRLEC VLMYKARGPGPGLCIVYRDCIAYAACHGPGPGPEWIERQTVLQHSFNGPGPGPINIS KSKAHKAIELGPGPGLRTLQQLFLSTLSFVGPGPGFHSIAGQYRGQCNTCGPGPGTT PIIHLKGDANILKGPGPGDWVMAIFGVNPTVAEGFGPGPGPRKLHELSSALEIPYGP GPGFKTLIKPATLYAHIQGPGPGTIPNSVQISVGYMTIGPGPGNGWFYVEAVIDRQT GGPGPGVLDFAFTDLTIVYRDGPGPGAKFVAAWTLKAAA (SEQ ID NO 125) B. ICCG6138 DNA sequence ATGGGCATGCAGGTGCAGATCCAGAGCCTGTTCCTGCTGCTGCTGTGGGTGCCCGGC AGCCGGGGCTTCTACAGCAAGGTGTCCGAGTTCCGGTGGAAGGCCGCCAGGACCGAG GTGTACCAGTTCGCCTTCCGGAACGCCGCCGTGACCACCAGATACCCCCTGCTGCGG AACGTGTTCACCTTCCCCAACCCCTTCCCTTTCAACTACACCAACTGGAAGTTCATC TACCTGAACGCCAGCGTGTACGGCGAGACCCTGGAAAAGGGAGCAGCCGTGATGTGC CGGCACTACAAGCGGAACGCCGTGTACGGCACCACACTGGAAAAGCTGAAGGTGGTG TTCATCTACATCCCCCTGTTCGGAGCCGCCAAGCTGCTGGAAAAACTGCTGTGCATC AACGGCACCGGCTGCAACGGCTGGTTCTACAACCAGACCGAGCCCGACACCAGCAAC TACAATGCTGCCGCCCCCTACCTGCACAGCAGACTGGTGGTGTTTGGGGCTGCCGCC CTGACCGACGTGAGCATCGCCTGCGTGTACAACGCCCACTACACAAATTGGAAATTC ATTTTTGGAGCCGCCTTCATCTATATTCCTCTGTTCGTGATCAAAGCCGCCGCTATG GTGATGCTGATGCTGGTGCGGTTCAAGAACGCCGCCAACACCGAGCTGTACAACCTG CTGATCAACTTCCTGTTCACCGACCTGACCATCGTGAACTTTCTCCTGTGTTTCTGC GTGCTCCTGAATGCCGCCACAACCCCCATCATCCACCTGAAGGGAGCCGCCAAACTG ACCAACAAGGGCATCTGCGACCTGAATGCCCTCCAGGACAAGATCCTGGACCACTAC AAGAACACCGGCATCCTGACCGTGACCTATGGAGCCGCTGCCGTGATGGACGACAGC GAGATCGCCTACAACAGCACCTGGCACTGGACCGGCTGTAACAAGAAGGCCGCCTCC TACTTCGGCATGAGCTTCATCCACTTCAAGCTGTCCAGCGCCCTGGAAATCCCCTAC AAGCTGTCCCAGATGGTGCAGTGGGCCTACAACTCCCTGGTGTTCCTGCTGTGTTTC AGCGTGAACGCAACCCTCTATGCCCACATCCAGTGCCTGAATGTGTTTACCTTCCCT CACGCCTTTCCCTTCAATGCCGCCGCCAGACAGATGAACATGAGCCAGTGGATCAAG AATGCCACCCTCCAGGAGATTGTCCTGCACGTCAATGCCGCCTTTACTGATCTGACT ATCGTGTACAACATCAGCTTCGCCGGCATCGTGACCAAGAAATACGTGGTGTGGGAC AGCATCTACTACATCAATTACTACATCACCGAGACCGGCATCTGGAAAGCTGCCGCC

10 Patent Application Publication Oct. 28, 2010 Sheet 9 of 17 US 2010/ Al TTCTACAGCCGGATCAGGGAGCTGAGGTTCAAAGTGTATCAGTTTGCTTTCAAAGAC CTGAAAGCCTTCCTGCTGTGCTTTTCCGTGTGCCTGAACGCCGCCTACCAGTTTGCC TTTAAGGATCTGTGCGTGAAGAGCGTGTATGGCACAACCCTGGAACGGAACAAAGTG TCTGAGTTCCGCTGGTACAGGTATAAGGCCGCCGAACTCGATCCCGTGGATCTGCTG TGTTACAAGAGCACTGCCGCCGCACTGTACTGGTATAGGAAGGCTGCCGCCGTGTAC GTGTGCGCCTTCGCCTGGCTGCTGGAGATCGTGCTGCACCTGGAACCCCAGAACGAG CTGGACCCTGTGGGCCCTGGCCCTGGCATCAGAATCCTCCAGGAACTGCTGATGGGC AGCTTCGGCATCGTGGGCCCAGGCCCCGGAACCGGCCGGTGCATCGCCTGTTGGCGG AGGCCCCGGACCGAGACAGGCCCTGGACCCGGCTGGAAGCACATCCGGCTGGAATGC GTGCTGATGTACAAGGCCAGGGGACCCGGCCCTGGCCTCTGTATCGTGTACCGCGAC TGCATCGCCTACGCCGCCTGCCACGGCCCAGGACCTGGCCCCGAGTGGATCGAGCGG CAGACCGTGCTCCAGCATAGCTTCAACGGACCCGGACCAGGCCCCATCAACATCAGC AAGAGCAAGGCCCACAAGGCCATCGAGCTGGGCCCTGGGCCCGGACTGCGGACCCTC CAGCAGCTGTTCCTGAGCACCCTGAGCTTCGTGGGACCTGGGCCAGGCTTCCACAGC ATCGCCGGCCAGTACCGGGGCCAGTGCAACACCTGCGGCCCAGGGCCAGGCACCACA CCTATTATTCACCTGAAGGGCGACGCCAACATCCTGAAGGGGCCAGGACCCGGCGAC TGGGTGATGGCCATCTTCGGCGTGAACCCCACCGTGGCCGAGGGCTTCGGACCTGGA CCTGGGCCTAGGAAGCTGCACGAGCTGTCCTCTGCCCTGGAAATTCCTTACGGCCCT GGCCCAGGCTTCAAGACCCTGATCAAGCCCGCCACACTGTATGCCCACATTCAGGGC CCTGGACCAGGCACCATCCCCAACAGCGTGCAGATCAGCGTGGGCTACATGACCATC GGACCAGGGCCTGGCAATGGCTGGTTCTACGTGGAGGCCGTGATCGACAGGCAGACC GGCGGACCTGGCCCAGGGGTGCTGGACTTCGCCTTTACAGACCTGACAATTGTGTAC CGGGACGGCCCTGGGCCTGGCGCCAAGTTCGTGGCCGCCTGGACCCTGAAGGCCGCT GCCTGA (SEQ ID NO 126) 102 FYSKVSEFRWKAARTEVYQFAFRNAAVTTRYPLLRNVFTFPNPFPFNYTNWKFIYLN ASVYGETLEKGAAVMCRHYKRNAVYGTTLEKLKVVFIYIPLFGAAKLLEKLLCINGT GCNGWFYNQTEPDTSNYNAAAPYLHSRLVVFGAAALTDVSIACVYNAHYTNWKFIFG AAFIYIPLFVIKAAAMVMLMLVRFKNAANTELYNLLINFLFTDLTIVNFLLCFCVLL NAATTPIIHLKGAAKLTNKGICDLNALQDKILDHYKNTGILTVTYGAAAVMDDSEIA YNSTWHWTGCNKKAASYFGMSFIHFKLSSALEIPYKLSQMVQWAYNSLVFLLCFSVN ATLYAHIQCLNVFTFPHAFPFNAAARQMNMSQWIKNATLQEIVLHVNAAFTDLTIVY NISFAGIVTKKYVVWDSIYYINYYITETGIWKAAAFYSRIRELRFKVYQFAFKDLKA FLLCFSVCLNAAYQFAFKDLCVKSVYGTTLERNKVSEFRWYRYKAAELDPVDLLCYK STAAALYWYRKAAAVYVCAFAWLLEIVLHLEPQNELDPVGPGPGIRILQELLMGSFG IVGPGPGTGRCIACWRRPRTETGPGPGWKHIRLECVLMYKARGPGPGLCIVYRDCIA YAACHGPGPGPEWIERQTVLQHSFNGPGPGPINISKSKAHKAIELGPGPGLRTLQQL FLSTLSFVGPGPGFHSIAGQYRGQCNTCGPGPGTTPIIHLKGDANILKGPGPGDWVM Al FGVNPTVAEGFGPGPGPRKLHELSSALEIPYGPGPGFKTLIKPATLYAHIQGPGP GTIPNSVQISVGYMTIGPGPGNGWFYVEAVIDRQTGGPGPGVLDFAFTDLTIVYRDG PGPGAKFVAAWTLKAAA (SEQ ID NO 158) FIGURE 6 cont.1

11 Patent Application Publication Oct. 28, 2010 Sheet 10 of 17 US 2010/ Al ij TTCTACAGCAAGGTGTCCGAGTTCCGGTGGAAGGCCGCCAGGACCGAGGTGTACCAG TTCGCCTTCCGGAACGCCGCCGTGACCACCAGATACCCCCTGCTGCGGAACGTGTTC ACCTTCCCCAACCCCTTCCCTTTCAACTACACCAACTGGAAGTTCATCTACCTGAAC GCCAGCGTGTACGGCGAGACCCTGGAAAAGGGAGCAGCCGTGATGTGCCGGCACTAC AAGCGGAACGCCGTGTACGGCACCACACTGGAAAAGCTGAAGGTGGTGTTCATCTAC ATCCCCCTGTTCGGAGCCGCCAAGCTGCTGGAAAAACTGCTGTGCATCAACGGCACC GGCTGCAACGGCTGGTTCTACAACCAGACCGAGCCCGACACCAGCAACTACAATGCT GCCGCCCCCTACCTGCACAGCAGACTGGTGGTGTTTGGGGCTGCCGCCCTGACCGAC GTGAGCATCGCCTGCGTGTACAACGCCCACTACACAAATTGGAAATTCATTTTTGGA GCCGCCTTCATCTATATTCCTCTGTTCGTGATCAAAGCCGCCGCTATGGTGATGCTG ATGCTGGTGCGGTTCAAGAACGCCGCCAACACCGAGCTGTACAACCTGCTGATCAAC TTCCTGTTCACCGACCTGACCATCGTGAACTTTCTCCTGTGTTTCTGCGTGCTCCTG AATGCCGCCACAACCCCCATCATCCACCTGAAGGGAGCCGCCAAACTGACCAACAAG GGCATCTGCGACCTGAATGCCCTCCAGGACAAGATCCTGGACCACTACAAGAACACC GGCATCCTGACCGTGACCTATGGAGCCGCTGCCGTGATGGACGACAGCGAGATCGCC TACAACAGCACCTGGCACTGGACCGGCTGTAACAAGAAGGCCGCCTCCTACTTCGGC ATGAGCTTCATCCACTTCAAGCTGTCCAGCGCCCTGGAAATCCCCTACAAGCTGTCC CAGATGGTGCAGTGGGCCTACAACTCCCTGGTGTTCCTGCTGTGTTTCAGCGTGAAC GCAACCCTCTATGCCCACATCCAGTGCCTGAATGTGTTTACCTTCCCTCACGCCTTT CCCTTCAATGCCGCCGCCAGACAGATGAACATGAGCCAGTGGATCAAGAATGCCACC CTCCAGGAGATTGTCCTGCACGTCAATGCCGCCTTTACTGATCTGACTATCGTGTAC AACATCAGCTTCGCCGGCATCGTGACCAAGAAATACGTGGTGTGGGACAGCATCTAC TACATCAATTACTACATCACCGAGACCGGCATCTGGAAAGCTGCCGCCTTCTACAGC CGGATCAGGGAGCTGAGGTTCAAAGTGTATCAGTTTGCTTTCAAAGACCTGAAAGCC TTCCTGCTGTGCTTTTCCGTGTGCCTGAACGCCGCCTACCAGTTTGCCTTTAAGGAT CTGTGCGTGAAGAGCGTGTATGGCACAACCCTGGAACGGAACAAAGTGTCTGAGTTC CGCTGGTACAGGTATAAGGCCGCCGAACTCGATCCCGTGGATCTGCTGTGTTACAAG AGCACTGCCGCCGCACTGTACTGGTATAGGAAGGCTGCCGCCGTGTACGTGTGCGCC TTCGCCTGGCTGCTGGAGATCGTGCTGCACCTGGAACCCCAGAACGAGCTGGACCCT GTGGGCCCTGGCCCTGGCATCAGAATCCTCCAGGAACTGCTGATGGGCAGCTTCGGC ATCGTGGGCCCAGGCCCCGGAACCGGCCGGTGCATCGCCTGTTGGCGGAGGCCCCGG ACCGAGACAGGCCCTGGACCCGGCTGGAAGCACATCCGGCTGGAATGCGTGCTGATG TACAAGGCCAGGGGACCCGGCCCTGGCCTCTGTATCGTGTACCGCGACTGCATCGCC TACGCCGCCTGCCACGGCCCAGGACCTGGCCCCGAGTGGATCGAGCGGCAGACCGTG CTCCAGCATAGCTTCAACGGACCCGGACCAGGCCCCATCAACATCAGCAAGAGCAAG GCCCACAAGGCCATCGAGCTGGGCCCTGGGCCCGGACTGCGGACCCTCCAGCAGCTG TTCCTGAGCACCCTGAGCTTCGTGGGACCTGGGCCAGGCTTCCACAGCATCGCCGGC CAGTACCGGGGCCAGTGCAACACCTGCGGCCCAGGGCCAGGCACCACACCTATTATT CACCTGAAGGGCGACGCCAACATCCTGAAGGGGCCAGGACCCGGCGACTGGGTGATG GCCATCTTCGGCGTGAACCCCACCGTGGCCGAGGGCTTCGGACCTGGACCTGGGCCT AGGAAGCTGCACGAGCTGTCCTCTGCCCTGGAAATTCCTTACGGCCCTGGCCCAGGC TTCAAGACCCTGATCAAGCCCGCCACACTGTATGCCCACATTCAGGGCCCTGGACCA GGCACCATCCCCAACAGCGTGCAGATCAGCGTGGGCTACATGACCATCGGACCAGGG CCTGGCAATGGCTGGTTCTACGTGGAGGCCGTGATCGACAGGCAGACCGGCGGACCT GGCCCAGGGGTGCTGGACTTCGCCTTTACAGACCTGACAATTGTGTACCGGGACGGC CCTGGGCCTGGCGCCAAGTTCGTGGCCGCCTGGACCCTGAAGGCCGCTGCC (SEQ ID NO 159) FIGURE 6 cont.2

12 Patent Application Publication Oct. 28, 2010 Sheet 11 of 17 US 2010/ Al FIGURE 7 A. ICCG6149 Amino acid sequence MGMQVQIQSLFLLLLWVPGSRGKSLFGMSLMKNSTAAALYWYKKAACYSLYGTTFKA AAVAWDSVYYMKSTDLRDHIDYNISDYRHYCYKAAQVVPAYNISKNGYNTFYIEFKL QDKIIDHYKAACLYLHIQSLNAAAATLQDIVLHGTVYVFCFLLNAILYAHIQCLNAA LYNLLIRCFKAAFVYIPLFLINTVSATQLVKNGTGCNGWFYNAATKYPLLKNVYVFC FLLPMNATLHDIILECVKAAALYGVSFSELKQVDYYGLYYGAYYMTDAGTWNAAPYA VCDKCFKQGAMLAVFKKAAAVVLLLVRYKNAAASYFGMSFIHFKAAKLLSKLLCVNA AAATMCRHYKRNAAASTVSVGTAKNAALSQMVQWAYKLTNTGLYNVNAAATCVSHRG LYNAAKSAIVTLTYKAAADSVYGDTLERNMYVCCHVPLNAARFHNIRGRFKAAFVVY RDSIPKNASLQDIEITCVKAVYDFAFRDLCIKYMLDLQPETVNAAAGTLGIVCPVNS VICFVNSKNATLEKLTNTGLYNAGLYYVHEGIRTYFVQGPGPGFLNTVAIPDSVQIL VGPGPGQRFHNIRGRWTGRCMGPGPGTNTGLYNLLIRCLRCQGPGPGIEFITFLGAL KSFLKGPGPGPEWIQRQTVLQHSFNGPGPGLFVVYRDSIPHAACHKGPGPGIRTLED LLMGTLGIVGPGPGLDLQPETTDLYCYEQGPGPGLQAIELQLTLETIYNGPGPGFQQ LFLNTLSFVCPWGPGPGWKHMRLECAIYYKARGPGPGLCTELQTTI HDI I LEGPGPG FKTLIQPFILYAHIQGPGPGLYWYKTGISNISEVYGPGPGEVFEFAFKDLFVVYRGP GPGHKAIELQMALQGLAQGPGPGAKFVAAWTLKAAA (SEQ ID NO 127) B. ICCG6149 DNA sequence ATGGGCATGCAGGTGCAGATCCAGAGCCTGTTCCTGCTGCTGCTGTGGGTGCCCGGC AGCCGGGGCAAGAGCCTGTTTGGCATGAGCCTGATGAAGAACAGCACCGCCGCTGCC CTCTATTGGTACAAAAAGGCCGCCTGCTACAGCCTGTACGGCACCACCTTCAAGGCT GCTGCCGTGGCCTGGGACAGCGTGTACTACATGAAGAGCACCGACCTGCGGGACCAC ATCGACTACAACATCAGCGACTACCGGCACTACTGCTACAAGGCCGCCCAGGTGGTG CCCGCCTACAACATCTCCAAGAACGGCTACAACACCTTCTACATCGAGTTCAAGCTC CAGGACAAGATCATCGACCACTACAAAGCCGCCTGCCTGTACCTGCACATCCAGAGT CTGAACGCAGCCGCTGCAACCCTCCAGGACATCGTGCTGCACGGCACCGTGTACGTG TTCTGCTTCCTGCTGAACGCCATCCTGTACGCCCACATCCAGTGTCTGAATGCCGCC CTGTACAACCTGCTGATCCGGTGCTTTAAGGCCGCCTTCGTGTACATCCCCCTGTTT CTGATCAACACCGTGAGCGCCACCCAGCTGGTGAAGAATGGCACCGGCTGCAACGGC TGGTTCTACAATGCCGCCACCAAGTACCCCCTGCTGAAGAACGTGTATGTGTTTTGT TTTCTGCTGCCCATGAACGCCACACTGCACGACATTATCCTGGAATGCGTCAAGGCC GCTGCCCTGTATGGCGTGAGCTTCAGCGAGCTGAAGCAGGTGGACTACTACGGCCTG TACTACGGCGCCTACTACATGACCGACGCCGGCACCTGGAATGCCGCCCCTTACGCC GTGTGCGACAAGTGCTTCAAGCAGGGCGCCATGCTGGCCGTGTTCAAGAAAGCCGCT GCCGTGGTGCTGCTGCTGGTGCGGTATAAGAATGCCGCCGCCAGCTACTTCGGCATG AGCTTCATCCACTTTAAAGCCGCCAAGCTGCTGTCTAAGCTGCTGTGCGTGAATGCC GCTGCTGCCACAATGTGCCGGCACTACAAGAGAAATGCCGCTGCCAGCACCGTGAGC GTGGGCACCGCCAAGAACGCCGCCCTGAGCCAGATGGTGCAGTGGGCCTACAAGCTG ACCAACACCGGCCTGTACAACGTGAACGCCGCTGCCACCTGCGTGAGCCACCGGGGC CTGTATAACGCCGCCAAGAGCGCCATCGTGACCCTGACCTATAAGGCCGCTGCCGAC AGCGTGTACGGCGACACCCTGGAACGGAACATGTACGTGTGCTGCCACGTGCCCCTG AATGCCGCCAGGTTCCACAACATCCGGGGCAGGTTCAAAGCCGCCTTTGTGGTGTAC

13 Patent Application Publication Oct. 28, 2010 Sheet 12 of 17 US 2010/ Al CGGGACAGCATCCCCAAGAATGCCAGCCTCCAGGATATTGAGATCACCTGTGTGAAG GCCGTGTACGACTTCGCCTTCCGGGACCTGTGCATCAAGTACATGCTGGACCTCCAG CCCGAGACAGTGAACGCCGCCGCTGGCACACTGGGCATCGTGTGCCCCGTGAACAGC GTGATCTGCTTCGTGAACAGCAAAAACGCCACCCTGGAAAAGCTGACAAATACAGGG CTGTACAATGCCGGCCTGTATTACGTGCACGAGGGCATCCGGACCTACTTCGTGCAG GGCCCAGGGCCAGGCTTCCTGAACACCGTGGCCATCCCCGACTCCGTGCAGATCCTG GTCGGCCCAGGACCAGGGCAGCGGTTCCACAATATCAGAGGCCGGTGGACCGGCAGA TGCATGGGCCCAGGACCTGGCACAAATACCGGACTGTATAATCTGCTGATTCGCTGC CTGCGGTGCCAGGGTCCAGGACCAGGCATCGAGTTTATCACCTTTCTGGGCGCCCTG AAGAGCTTCCTGAAAGGACCTGGACCAGGACCCGAGTGGATTCAGCGGCAGACCGTG CTCCAGCACAGCTTCAACGGACCCGGACCCGGCCTGTTCGTGGTGTACAGAGACTCC ATCCCCCACGCCGCCTGTCACAAGGGACCTGGACCAGGCATCAGGACCCTGGAGGAC CTGCTGATGGGCACCCTGGGCATTGTGGGGCCTGGACCTGGACTGGATCTCCAGCCT GAAACCACCGACCTGTACTGCTACGAGCAGGGGCCAGGACCTGGGCTCCAGGCTATC GAACTCCAGCTGACCCTGGAAACCATCTACAATGGCCCCGGACCAGGCTTCCAGCAG CTGTTCCTGAATACCCTGAGCTTCGTGTGCCCTTGGGGACCAGGGCCCGGATGGAAG CACATGCGGCTGGAATGCGCCATCTACTACAAGGCCAGAGGCCCAGGACCCGGACTG TGCACCGAACTCCAGACCACCATCCACGACATCATTCTGGAAGGACCAGGGCCAGGC TTTAAGACCCTGATCCAGCCCTTCATTCTGTATGCCCACATTCAGGGACCTGGGCCT GGCCTGTATTGGTATAAGACCGGCATCAGCAACATCTCCGAGGTGTACGGGCCTGGA CCAGGCGAGGTGTTCGAGTTCGCCTTCAAGGATCTGTTTGTGGTGTATAGAGGCCCC GGACCTGGCCACAAGGCCATTGAACTCCAGATGGCCCTCCAGGGGCTGGCCCAGGGA CCAGGCCCTGGCGCCAAGTTCGTGGCCGCCTGGACCCTGAAAGCCGCCGCCTGA (SEQ ID NO 128) C. KSLFGMSLMKNSTAAALYWYKKAACYSLYGTTFKAAAVAWDSVYYMKSTDLRDHIDY NISDYRHYCYKAAQVVPAYNISKNGYNTFYIEFKLQDKIIDHYKAACLYLHIQSLNA AAATLQDIVLHGTVYVFCFLLNAILYAHIQCLNAALYNLLIRCFKAAFVYIPLFLIN TVSATQLVKNGTGCNGWFYNAATKYPLLKNVYVFCFLLPMNATLHDIILECVKAAAL YGVSFSELKQVDYYG LYYGAYYMTDAGTWNAAPYAVCDKCFKQGAM LAVFKKAAAVV LLLVRYKNAAASYFGMSFIHFKAAKLLSKLLCVNAAAATMCRHYKRNAAASTVSVGT AKNAALSQMVQWAYKLTNTGLYNVNAAATCVSHRGLYNAAKSAIVTLTYKAAADSVY GDTLERNMYVCCHVPLNAARFHNIRGRFKAAFVVYRDSIPKNASLQDIEITCVKAVY DFAFRDLCIKYMLDLQPETVNAAAGTLGIVCPVNSVICFVNSKNATLEKLTNTGLYN AGLYYVHEGIRTYFVQGPGPGFLNTVAIPDSVQILVGPGPGQRFHNIRGRWTGRCMG PGPGTNTGLYNLLIRCLRCQGPGPGIEFITFLGALKSFLKGPGPGPEWIQRQTVLQH SFNGPGPGLFVVYRDSIPHAACHKGPGPGIRTLEDLLMGTLGIVGPGPGLDLQPETT DLYCYEQGPGPGLQAIELQLTLETIYNGPGPGFQQLFLNTLSFVCPWGPGPGWKHMR LECAIYYKARGPGPGLCTELQTTIHDIILEGPGPGFKTLIQPFILYAHIQGPGPGLY WYKTGISNISEVYGPGPGEVFEFAFKDLFVVYRGPGPGHKAIELQMALQGLAQGPGP GAKFVAAWTLKAAA (SEQ ID NO 160) FIGURE 7 cont.1

14 Patent Application Publication Oct. 28, 2010 Sheet 13 of 17 US 2010/ Al D. AAGAGCCTGTTTGGCATGAGCCTGATGAAGAACAGCACCGCCGCTGCCCTCTATTGG TACAAAAAGGCCGCCTGCTACAGCCTGTACGGCACCACCTTCAAGGCTGCTGCCGTG GCCTGGGACAGCGTGTACTACATGAAGAGCACCGACCTGCGGGACCACATCGACTAC AACATCAGCGACTACCGGCACTACTGCTACAAGGCCGCCCAGGTGGTGCCCGCCTAC AACATCTCCAAGAACGGCTACAACACCTTCTACATCGAGTTCAAGCTCCAGGACAAG ATCATCGACCACTACAAAGCCGCCTGCCTGTACCTGCACATCCAGAGTCTGAACGCA GCCGCTGCAACCCTCCAGGACATCGTGCTGCACGGCACCGTGTACGTGTTCTGCTTC CTGCTGAACGCCATCCTGTACGCCCACATCCAGTGTCTGAATGCCGCCCTGTACAAC CTGCTGATCCGGTGCTTTAAGGCCGCCTTCGTGTACATCCCCCTGTTTCTGATCAAC ACCGTGAGCGCCACCCAGCTGGTGAAGAATGGCACCGGCTGCAACGGCTGGTTCTAC AATGCCGCCACCAAGTACCCCCTGCTGAAGAACGTGTATGTGTTTTGTTTTCTGCTG CCCATGAACGCCACACTGCACGACATTATCCTGGAATGCGTCAAGGCCGCTGCCCTG TATGGCGTGAGCTTCAGCGAGCTGAAGCAGGTGGACTACTACGGCCTGTACTACGGC GCCTACTACATGACCGACGCCGGCACCTGGAATGCCGCCCCTTACGCCGTGTGCGAC AAGTGCTTCAAGCAGGGCGCCATGCTGGCCGTGTTCAAGAAAGCCGCTGCCGTGGTG CTGCTGCTGGTGCGGTATAAGAATGCCGCCGCCAGCTACTTCGGCATGAGCTTCATC CACTTTAAAGCCGCCAAGCTGCTGTCTAAGCTGCTGTGCGTGAATGCCGCTGCTGCC ACAATGTGCCGGCACTACAAGAGAAATGCCGCTGCCAGCACCGTGAGCGTGGGCACC GCCAAGAACGCCGCCCTGAGCCAGATGGTGCAGTGGGCCTACAAGCTGACCAACACC GGCCTGTACAACGTGAACGCCGCTGCCACCTGCGTGAGCCACCGGGGCCTGTATAAC GCCGCCAAGAGCGCCATCGTGACCCTGACCTATAAGGCCGCTGCCGACAGCGTGTAC GGCGACACCCTGGAACGGAACATGTACGTGTGCTGCCACGTGCCCCTGAATGCCGCC AGGTTCCACAACATCCGGGGCAGGTTCAAAGCCGCCTTTGTGGTGTACCGGGACAGC ATCCCCAAGAATGCCAGCCTCCAGGATATTGAGATCACCTGTGTGAAGGCCGTGTAC GACTTCGCCTTCCGGGACCTGTGCATCAAGTACATGCTGGACCTCCAGCCCGAGACA GTGAACGCCGCCGCTGGCACACTGGGCATCGTGTGCCCCGTGAACAGCGTGATCTGC TTCGTGAACAGCAAAAACGCCACCCTGGAAAAGCTGACAAATACAGGGCTGTACAAT GCCGGCCTGTATTACGTGCACGAGGGCATCCGGACCTACTTCGTGCAGGGCCCAGGG CCAGGCTTCCTGAACACCGTGGCCATCCCCGACTCCGTGCAGATCCTGGTCGGCCCA GGACCAGGGCAGCGGTTCCACAATATCAGAGGCCGGTGGACCGGCAGATGCATGGGC CCAGGACCTGGCACAAATACCGGACTGTATAATCTGCTGATTCGCTGCCTGCGGTGC CAGGGTCCAGGACCAGGCATCGAGTTTATCACCTTTCTGGGCGCCCTGAAGAGCTTC CTGAAAGGACCTGGACCAGGACCCGAGTGGATTCAGCGGCAGACCGTGCTCCAGCAC AGCTTCAACGGACCCGGACCCGGCCTGTTCGTGGTGTACAGAGACTCCATCCCCCAC GCCGCCTGTCACAAGGGACCTGGACCAGGCATCAGGACCCTGGAGGACCTGCTGATG GGCACCCTGGGCATTGTGGGGCCTGGACCTGGACTGGATCTCCAGCCTGAAACCACC GACCTGTACTGCTACGAGCAGGGGCCAGGACCTGGGCTCCAGGCTATCGAACTCCAG CTGACCCTGGAAACCATCTACAATGGCCCCGGACCAGGCTTCCAGCAGCTGTTCCTG AATACCCTGAGCTTCGTGTGCCCTTGGGGACCAGGGCCCGGATGGAAGCACATGCGG CTGGAATGCGCCATCTACTACAAGGCCAGAGGCCCAGGACCCGGACTGTGCACCGAA CTCCAGACCACCATCCACGACATCATTCTGGAAGGACCAGGGCCAGGCTTTAAGACC CTGATCCAGCCCTTCATTCTGTATGCCCACATTCAGGGACCTGGGCCTGGCCTGTAT TGGTATAAGACCGGCATCAGCAACATCTCCGAGGTGTACGGGCCTGGACCAGGCGAG GTGTTCGAGTTCGCCTTCAAGGATCTGTTTGTGGTGTATAGAGGCCCCGGACCTGGC CACAAGGCCATTGAACTCCAGATGGCCCTCCAGGGGCTGGCCCAGGGACCAGGCCCT GGCGCCAAGTTCGTGGCCGCCTGGACCCTGAAAGCCGCCGCC (SEQ ID NO 161) FIGURE 7 cont.2

15 Patent Application Publication Oct. 28, 2010 Sheet 14 of 17 US 2010/ Al FIGURE 8 A. ICCG6150 Amino acid sequence MGMQVQIQSLFLLLLWVPGSRGATCVSHRGLYNAASTDLRDHIDYNAAAATMCRHYK RNAILYAHIQCLNAAAGTLGIVCPVNAAACYSLYGTTFKAAADSVYGDTLERNQVVP AYNISKNAALYNLLIRCFKAAFVYIPLFLINYYMTDAGTWGAVVLLLVRYKNAAISD YRHYCYKAATVSATQLVKKASTAAALYWYKKAAFVVYRDSIPKNASYFGMSFIHFKA AYMLDLQPETVNAAVYDFAFRDLCIKAALQDKIIDHYKAATLHDIILECVKKLTNTG LYNVGAAASVICFVNSKGAAAMYVCCHVPLNASLQDIEITCVKCLYLHIQSLNAATK YPLLKNVYVFCFLLPMNAKQGAMLAVFKKAALSQMVQWAYKAAPYAVCDKCFKAATV YVFCFLLNAAAATLQDIVLHGAKSLFGMSLMKNGTGCNGWFYNARFHNIRGRFKAAK LLSKLLCVNAAASTVSVGTAKNVAWDSVYYMKAAAGYNTFYIEFKAAALYGVSFSEL KQVDYYGLYYNAAKSAIVTLTYKAAATLEKLTNTGLYNAGLYYVHEGIRTYFVQGPG PGFLNTVAIPDSVQILVGPGPGQRFHNIRGRWTGRCMGPGPGTNTGLYNLLIRCLRC QGPGPGIEFITFLGALKSFLKGPGPGPEWIQRQTVLQHSFNGPGPGLFVVYRDSIPH AACHKGPGPGIRTLEDLLMGTLGIVGPGPGLDLQPETTDLYCYEQGPGPGLQAIELQ LTLETIYNGPGPGFQQLFLNTLSFVCPWGPGPGWKHMRLECAIYYKARGPGPGLCTE LQTTIHDIILEGPGPGFKTLIQPFILYAHIQGPGPGLYWYKTGISNISEVYGPGPGE VFEFAFKDLFVVYRGPGPGHKAIELQMALQGLAQGPGPGAKFVAAWTLKAAA (SEQ ID NO 129) B. ICCG6150 DNA sequence ATGGGCATGCAGGTGCAGATCCAGAGCCTGTTCCTGCTGCTGCTGTGGGTGCCCGGC AGCAGAGGCGCCACCTGCGTGAGCCACAGGGGCCTCTACAACGCCGCCAGCACCGAC CTGCGGGACCACATCGACTACAATGCTGCTGCCGCTACAATGTGCCGGCACTACAAG CGGAACGCCATCCTGTACGCCCACATCCAGTGCCTGAATGCTGCCGCTGGCACACTG GGCATCGTGTGCCCCGTGAATGCCGCCGCCTGCTACAGCCTGTACGGCACCACCTTC AAGGCCGCTGCCGACTCCGTGTACGGCGACACCCTGGAACGGAACCAGGTGGTGCCC GCCTACAACATCTCTAAGAATGCCGCTCTGTACAACCTGCTGATCCGGTGCTTTAAG GCTGCCTTCGTGTACATCCCCCTGTTTCTGATCAACTACTACATGACCGACGCCGGC ACATGGGGAGCCGTGGTGCTGCTGCTGGTGCGGTACAAGAATGCCGCCATCAGCGAC TACCGGCACTACTGCTACAAGGCCGCCACCGTCAGCGCCACCCAGCTGGTGAAGAAG GCCAGCACAGCCGCCGCTCTCTATTGGTATAAAAAAGCCGCCTTTGTGGTGTACCGG GACAGCATCCCCAAGAACGCCAGCTACTTCGGCATGAGCTTCATCCACTTCAAAGCC GCCTACATGCTGGACCTCCAGCCCGAGACCGTGAACGCTGCCGTGTACGACTTCGCC TTCCGGGACCTGTGCATTAAAGCCGCACTCCAGGACAAGATCATCGACCATTATAAA GCAGCCACCCTGCATGATATTATTCTGGAATGCGTGAAGAAGCTGACCAACACCGGC CTCTATAACGTGGGAGCCGCCGCCTCTGTGATCTGCTTCGTGAACAGCAAGGGGGCT GCCGCCATGTATGTGTGCTGCCACGTGCCCCTGAACGCCTCTCTCCAGGATATTGAG ATCACCTGTGTGAAGTGCCTGTACCTGCACATTCAGTCTCTGAATGCCGCCACCAAG TACCCCCTGCTGAAGAACGTGTATGTCTTTTGCTTCCTGCTGCCCATGAACGCCAAG CAGGGCGCCATGCTGGCCGTGTTCAAAAAGGCCGCCCTGAGCCAGATGGTGCAGTGG GCCTACAAAGCCGCCCCTTACGCCGTGTGCGACAAGTGTTTTAAGGCCGCCACAGTG TACGTGTTTTGTTTTCTGCTGAATGCCGCTGCCGCCACCCTCCAGGACATCGTGCTG CACGGCGCCAAGTCCCTGTTCGGCATGTCCCTGATGAAGAATGGCACCGGCTGCAAC GGCTGGTTCTACAACGCCCGGTTCCACAACATCCGGGGCAGGTTTAAAGCCGCCAAG

16 Patent Application Publication Oct. 28, 2010 Sheet 15 of 17 US 2010/ Al CTGCTGTCTAAGCTGCTGTGTGTGAACGCCGCCGCTTCCACCGTGAGCGTGGGCACC GCCAAGAACGTGGCCTGGGACAGCGTGTACTACATGAAAGCAGCAGCCGGGTACAAC ACCTTCTACATCGAGTTTAAAGCTGCCGCCCTGTACGGCGTGAGCTTCAGCGAGCTG AAGCAGGTGGACTACTACGGCCTGTACTATAACGCCGCCAAGAGCGCCATCGTGACC CTGACCTATAAAGCCGCCGCCACACTGGAAAAGCTGACCAATACAGGGCTGTACAAT GCCGGCCTGTATTACGTGCACGAGGGCATCCGGACCTACTTCGTGCAGGGCCCAGGG CCAGGCTTCCTGAACACCGTGGCCATCCCCGACTCCGTGCAGATCCTGGTCGGCCCA GGACCAGGGCAGCGGTTCCACAATATCAGAGGCCGGTGGACCGGCAGATGCATGGGC CCAGGACCTGGCACAAATACCGGACTGTATAATCTGCTGATTCGCTGCCTGCGGTGC CAGGGTCCAGGACCAGGCATCGAGTTTATCACCTTTCTGGGCGCCCTGAAGAGCTTC CTGAAAGGACCTGGACCAGGACCCGAGTGGATTCAGCGGCAGACCGTGCTCCAGCAC AGCTTCAACGGACCCGGACCCGGCCTGTTCGTGGTGTACAGAGACTCCATCCCCCAC GCCGCCTGTCACAAGGGACCTGGACCAGGCATCAGGACCCTGGAGGACCTGCTGATG GGCACCCTGGGCATTGTGGGGCCTGGACCTGGACTGGATCTCCAGCCTGAAACCACC GACCTGTACTGCTACGAGCAGGGGCCAGGACCTGGGCTCCAGGCTATCGAACTCCAG CTGACCCTGGAAACCATCTACAATGGCCCCGGACCAGGCTTCCAGCAGCTGTTCCTG AATACCCTGAGCTTCGTGTGCCCTTGGGGACCAGGGCCCGGATGGAAGCACATGCGG CTGGAATGCGCCATCTACTACAAGGCCAGAGGCCCAGGACCCGGACTGTGCACCGAA CTCCAGACCACCATCCACGACATCATTCTGGAAGGACCAGGGCCAGGCTTTAAGACC CTGATCCAGCCCTTCATTCTGTATGCCCACATTCAGGGACCTGGGCCTGGCCTGTAT TGGTATAAGACCGGCATCAGCAACATCTCCGAGGTGTACGGGCCTGGACCAGGCGAG GTGTTCGAGTTCGCCTTCAAGGATCTGTTTGTGGTGTATAGAGGCCCCGGACCTGGC CACAAGGCCATTGAACTCCAGATGGCCCTCCAGGGGCTGGCCCAGGGACCAGGCCCT GGCGCCAAGTTCGTGGCCGCCTGGACCCTGAAAGCCGCCGCCTGA (SEQ ID NO 130) C. ATCVSHRGLYNAASTDLRDHIDYNAAAATMCRHYKRNAILYAHIQCLNAAAGTLGIV CPVNAAACYSLYGTTFKAAADSVYGDTLERNQVVPAYNISKNAALYNLLIRCFKAAF VYIPLFLINYYMTDAGTWGAVVLLLVRYKNAAISDYRHYCYKAATVSATQLVKKAST AAALYWYKKAAFVVYRDSIPKNASYFGMSFIHFKAAYMLDLQPETVNAAVYDFAFRD LCIKAALQDKIIDHYKAATLHDIILECVKKLTNTGLYNVGAAASVICFVNSKGAAAM YVCCHVPLNASLQDIEITCVKCLYLHIQSLNAATKYPLLKNVYVFCFLLPMNAKQGA MLAVFKKAALSQMVQWAYKAAPYAVCDKCFKAATVYVFCFLLNAAAATLQDIVLHGA KSLFGMSLMKNGTGCNGWFYNARFHNIRGRFKAAKLLSKLLCVNAAASTVSVGTAKN VAWDSVYYMKAAAGYNTFYIEFKAAALYGVSFSELKQVDYYGLYYNAAKSAIVTLTY KAAATLEKLTNTGLYNAGLYYVHEGIRTYFVQGPGPGFLNTVAIPDSVQILVGPGPG QRFHNIRGRWTGRCMGPGPGTNTGLYNLLIRCLRCQGPGPGIEFITFLGALKSFLKG PGPGPEWIQRQTVLQHSFNGPGPGLFVVYRDSIPHAACHKGPGPGIRTLEDLLMGTL GIVGPGPGLDLQPETTDLYCYEQGPGPGLQAIELQLTLETIYNGPGPGFQQLFLNTL SFVCPWGPGPGWKHMRLECAIYYKARGPGPGLCTELQTTIHDIILEGPGPGFKTLIQ PFILYAHIQGPGPGLYWYKTGISNISEVYGPGPGEVFEFAFKDLFVVYRGPGPGHKA IELQMALQGLAQGPGPGAKFVAAWTLKAAA (SEQ ID NO 162) FIGURE 8 cont.1

17 Patent Application Publication Oct. 28, 2010 Sheet 16 of 17 US 2010/ Al IM GCCACCTGCGTGAGCCACAGGGGCCTCTACAACGCCGCCAGCACCGACCTGCGGGAC CACATCGACTACAATGCTGCTGCCGCTACAATGTGCCGGCACTACAAGCGGAACGCC ATCCTGTACGCCCACATCCAGTGCCTGAATGCTGCCGCTGGCACACTGGGCATCGTG TGCCCCGTGAATGCCGCCGCCTGCTACAGCCTGTACGGCACCACCTTCAAGGCCGCT GCCGACTCCGTGTACGGCGACACCCTGGAACGGAACCAGGTGGTGCCCGCCTACAAC ATCTCTAAGAATGCCGCTCTGTACAACCTGCTGATCCGGTGCTTTAAGGCTGCCTTC GTGTACATCCCCCTGTTTCTGATCAACTACTACATGACCGACGCCGGCACATGGGGA GCCGTGGTGCTGCTGCTGGTGCGGTACAAGAATGCCGCCATCAGCGACTACCGGCAC TACTGCTACAAGGCCGCCACCGTCAGCGCCACCCAGCTGGTGAAGAAGGCCAGCACA GCCGCCGCTCTCTATTGGTATAAAAAAGCCGCCTTTGTGGTGTACCGGGACAGCATC CCCAAGAACGCCAGCTACTTCGGCATGAGCTTCATCCACTTCAAAGCCGCCTACATG CTGGACCTCCAGCCCGAGACCGTGAACGCTGCCGTGTACGACTTCGCCTTCCGGGAC CTGTGCATTAAAGCCGCACTCCAGGACAAGATCATCGACCATTATAAAGCAGCCACC CTGCATGATATTATTCTGGAATGCGTGAAGAAGCTGACCAACACCGGCCTCTATAAC GTGGGAGCCGCCGCCTCTGTGATCTGCTTCGTGAACAGCAAGGGGGCTGCCGCCATG TATGTGTGCTGCCACGTGCCCCTGAACGCCTCTCTCCAGGATATTGAGATCACCTGT GTGAAGTGCCTGTACCTGCACATTCAGTCTCTGAATGCCGCCACCAAGTACCCCCTG CTGAAGAACGTGTATGTCTTTTGCTTCCTGCTGCCCATGAACGCCAAGCAGGGCGCC ATGCTGGCCGTGTTCAAAAAGGCCGCCCTGAGCCAGATGGTGCAGTGGGCCTACAAA GCCGCCCCTTACGCCGTGTGCGACAAGTGTTTTAAGGCCGCCACAGTGTACGTGTTT TGTTTTCTGCTGAATGCCGCTGCCGCCACCCTCCAGGACATCGTGCTGCACGGCGCC AAGTCCCTGTTCGGCATGTCCCTGATGAAGAATGGCACCGGCTGCAACGGCTGGTTC TACAACGCCCGGTTCCACAACATCCGGGGCAGGTTTAAAGCCGCCAAGCTGCTGTCT AAGCTGCTGTGTGTGAACGCCGCCGCTTCCACCGTGAGCGTGGGCACCGCCAAGAAC GTGGCCTGGGACAGCGTGTACTACATGAAAGCAGCAGCCGGGTACAACACCTTCTAC ATCGAGTTTAAAGCTGCCGCCCTGTACGGCGTGAGCTTCAGCGAGCTGAAGCAGGTG GACTACTACGGCCTGTACTATAACGCCGCCAAGAGCGCCATCGTGACCCTGACCTAT AAAGCCGCCGCCACACTGGAAAAGCTGACCAATACAGGGCTGTACAATGCCGGCCTG TATTACGTGCACGAGGGCATCCGGACCTACTTCGTGCAGGGCCCAGGGCCAGGCTTC CTGAACACCGTGGCCATCCCCGACTCCGTGCAGATCCTGGTCGGCCCAGGACCAGGG CAGCGGTTCCACAATATCAGAGGCCGGTGGACCGGCAGATGCATGGGCCCAGGACCT GGCACAAATACCGGACTGTATAATCTGCTGATTCGCTGCCTGCGGTGCCAGGGTCCA GGACCAGGCATCGAGTTTATCACCTTTCTGGGCGCCCTGAAGAGCTTCCTGAAAGGA CCTGGACCAGGACCCGAGTGGATTCAGCGGCAGACCGTGCTCCAGCACAGCTTCAAC GGACCCGGACCCGGCCTGTTCGTGGTGTACAGAGACTCCATCCCCCACGCCGCCTGT CACAAGGGACCTGGACCAGGCATCAGGACCCTGGAGGACCTGCTGATGGGCACCCTG GGCATTGTGGGGCCTGGACCTGGACTGGATCTCCAGCCTGAAACCACCGACCTGTAC TGCTACGAGCAGGGGCCAGGACCTGGGCTCCAGGCTATCGAACTCCAGCTGACCCTG GAAACCATCTACAATGGCCCCGGACCAGGCTTCCAGCAGCTGTTCCTGAATACCCTG AGCTTCGTGTGCCCTTGGGGACCAGGGCCCGGATGGAAGCACATGCGGCTGGAATGC GCCATCTACTACAAGGCCAGAGGCCCAGGACCCGGACTGTGCACCGAACTCCAGACC ACCATCCACGACATCATTCTGGAAGGACCAGGGCCAGGCTTTAAGACCCTGATCCAG CCCTTCATTCTGTATGCCCACATTCAGGGACCTGGGCCTGGCCTGTATTGGTATAAG ACCGGCATCAGCAACATCTCCGAGGTGTACGGGCCTGGACCAGGCGAGGTGTTCGAG TTCGCCTTCAAGGATCTGTTTGTGGTGTATAGAGGCCCCGGACCTGGCCACAAGGCC ATTGAACTCCAGATGGCCCTCCAGGGGCTGGCCCAGGGACCAGGCCCTGGCGCCAAG TTCGTGGCCGCCTGGACCCTGAAAGCCGCCGCC (SEQ ID NO 163) FIGURE 8 cont.2

18 Patent Application Publication Oct. 28, 2010 Sheet 17 of 17 US 2010/ Al FIGURE 9

19 HPV POLYEPITOPE CONSTRUCTS AND USES THEREOF FIELD OF THE INVENTION [0001] The present invention is directed to Human Papillomavirus (HPV) polyepitope constructs and the use thereof for the prevention and/or treatment of HPV infection. BACKGROUND OF THE INVENTION [0002] Cancer of the cervix uteri is the second most common cancer among women worldwide, with an estimated 493,000 new cases and 274,000 deaths in The field of cervical cancer prevention is rapidly evolving as a consequence of the identification of the cause of the disease: a limited number of viral types from the family of the Human Papillomaviruses (HPV). Indeed, HPV has been recognized as a cause of cervical cancer, and 2 of the oncogenic types, 16 and 18, are together responsible for 70% of the world's cervical cancer cases. [0003] Recently the use of 2 prophylactic vaccines was licensed. Nevertheless, it is likely to be decades before the impact of HPV vaccination on the incidence of cervical cancer can be evaluated. Optimally, these vaccines should be administered before sexual debut and HPV infection. As such, they are of no benefit for women with already existing HPV infection. Treatment (surgery) for HPV infection is often unsatisfactory because of persistence of virus after treatment and recurrence of clinically apparent disease is common. The treatment may require frequent visits to clinics and is not directed at elimination of the virus but at clearing warts. Moreover, it is expected that less prevalent, oncogenic HPV genotypes will take over at least in part the place from the currently targeted HPV 16 and 18 genotypes. Women with pre-carcinogenic lesions resulting from the widespread HPV infections today represent a highly unmet need. [0004] Thus, a need exists for an efficacious vaccine to prevent and/or treat persistent HPV infection and to prevent cancer that is associated with HPV infection. Effective HPV vaccines would be a significant advance in the control of sexually transmissible infections and could also protect against clinical disease, particularly cancers such as cervical cancer. (see, e.g., Rowen, P. and Lacey, C., Dermatologic Clinics 16 (4): ,1998). [0005] In the majority of individuals, HPV infections presumably induce strong, local, cell-mediated immunity that results in clearance of the virus and protection against subsequent infection. Virus-specific, human leukocyte antigen (HLA) class I-restricted cytotoxic T lymphocytes (CTL) and HLA class II-restricted helper T lymphocytes (HTL) are known to play a major role in the prevention of chronic infection and in viral clearance in vivo (Houssaint et al., 2001; Graters et al., 2002; Tsai et al., 1997; Murray et al., 1992; Tigges et al., 1992; Bowen and Walker, 2005). [0006] A therapeutic vaccine candidate targeting HPV should elicit strong and multi-specific cellular immune responses. The induction of a strong HPV-specific cellular response-comprising activity of cytotoxic T-cells (CTL) and helper T-cells (HTL) may be achieved using an epitopebased vaccine approach. [0007] The polyepitope approach to vaccine development is to rationally create a multi-specific cellular response, causing the immune system to be specifically stimulated against multiple selected epitopes that meet stringent criteria. These include CTL epitopes that are presented by MHC-I and are recognized by cytotoxic T-cells, and HTL epitopes that bind MHC II and are recognized by helper T-cells. The epitopes are selected in view of their capacity to elicit responses in humans, thereby aiming for a large population coverage (by targeting major HLA class-i alleles as well as major HLA class-ii alleles). [0008] The technology relevant to polyepitope vaccines is developing and a number of different approaches are available which allow simultaneous delivery of multiple epitopes. Several independent studies have established that induction of simultaneous immune responses against multiple and individual peptides can be achieved (Doolan et al (1997), Bertoni and colleagues (1997)). In terms of immunization with polyepitope nucleic acid vaccines, several examples have been reported where multiple T cell responses were induced (Thomson et al., 1995; Woodberry et al., 1999; Mateo et al., 1999; Ishioka et al., 1999; W004/031210, Innogenetics N. V. et al.). [0009] The efforts to develop an effective treatment for HPV-related disease are narrowly focused. Most studies are concentrating on the HPV type 16 E6 and/or E7 protein. Also W005/ (Pharmexa et al.) discloses HPV polyepitope constructs focussing on E6 and E7, and additionally El and E2 proteins. During the papillomavirus life cycle, the HPV proteins (El, E2, E4, E5, E6, E7, Ll and L2) are differentially expressed. Moreover, during progression from CIN1 to CIN3, the extent of expression of the different HPV proteins is changing (Doorbar, 2005). Targeting all 6 early proteins (El, E2, E4, E5, E6 and E7) thus provides a way to induce efficient immune responses directed to all stages of the virus life cycle, irrespective of the CIN grade. [0010] Although E4 and E5 were screened for immunogenic epitopes, WO05/ was unsuccessful in obtaining reactive peptides. It is indeed known that most of the HPV proteins are comparatively small and might therefore not comprise many reactive epitopes. The present inventors however have now determined several immunogenic epitopes in the E4 and E5 proteins of the high risk HPV genotypes HPV16, 18, 31 and 45. Moreover, the present inventors were successful in creating a potent, multi-specific and full-spectrum vaccine addressing the different stages of HPV infection, and thereby broadening the treatment window. Where others, focusing on E6 and/or E7 are mainly targeting CIN2 and CIN3, this vaccine allows to treat earlier stages of disease as well as persistent infection, thereby further reducing the chance of developing cervical cancer. [0011] The polyepitope constructs are designed to induce an immune response to at least 4 distinct CTL and 1-3 HTL epitopes per HPV genotype in the majority of subjects infected with one of the four most prevalent, high risk HPV genotypes (HPV16, 18, 31 and 45) irrespective of their ethnic origin. SUMMARY OF THE INVENTION [0012] The present invention encompasses epitopes derived from the El, E2, E4, E5, E6 and/or E7 protein of the Human Papillomavirus (HPV). Each of the epitopes given in Tables 1 and 2, or any combination of two, more or all of these epitopes, are part of the invention, as well as their application in the treatment and/or prevention of HPV infection or HPVrelated disease. The epitopes are those which elicit a HLA class I- and/or class II-restricted T lymphocyte response in an immunized host.

20 2 [0013] In a particular embodiment, the present invention relates to an isolated CTL inducing peptide derived from a Human Papillomavirus protein, consisting of 8 to 13 amino acids and comprising the sequence represented by SEQ ID NO More specific, the invention encompasses an isolated CTL inducing peptide derived from the Human Papillomavirus protein E4 or E5, consisting of 8 to 13 amino acids and comprising the sequence represented by SEQ ID NO 8, 17, 29, 42, 43, 51, 64, 74, 75, 81 and 86. [0014] The invention also covers an isolated polyepitope construct comprising one or more of the herein described CTL inducing peptides. [0015] The present invention is furthermore directed to a polynucleotide, a polypeptide, a vector or a composition comprising a polyepitope construct encoding or comprising specifically selected epitopes derived of HPV. [0016] In one embodiment, the polyepitope construct encodes or comprises at least the following HPV derived CTL epitopes: SEQ ID NO 1 to 44, and/or the polyepitope construct encodes or comprises at least the following HPV CTL epitopes: SEQ ID NO 1, 23, 39 and 45 to 88. In another embodiment, the current invention relates to a polynucleotide comprising a polyepitope construct comprising nucleic acids encoding all the epitopes given in Table 1 (SEQ ID NO 1-88). Specifically, the construct does not encode a full-length protein from HPV. [0017] In a further embodiment, the polyepitope construct of the invention further encodes or comprises at least one CTL and/or HTL epitope. Preferably, the epitopes are isolated. In a specific embodiment, the at least one CTL and/or HTL epitope is derived from HPV. More specific, the at least one HTL epitope is selected from the group consisting of SEQ ID NO 89 to 121. Preferably, the polyepitope construct furthermore comprises a PADRE epitope. Specifically, the PADRE epitope is characterized by SEQ ID NO 122. [0018] Optionally, the epitopes inthe polyepitope construct are linked to each other by one or more, preferably 1 to 8, spacer amino acids. Ina specific embodiment, the one or more spacer amino acids are selected from the group consisting of: K, R, N, Q, G, A, S, C, G, P, and T. More specifically, the spacer between one or more CTL epitopes is selected from the group consisting of G, K, A or N, and the spacer between one or more HTL epitopes is selected from the group consisting of G, N and P. [0019] In a further embodiment, the CTL and/or HTL epitopes comprised in the polyepitope construct are sorted to minimize the number of CTL and/or HTL junctional epitopes. [0020] Specifically, the HPV CTL epitopes are directly or indirectly linked in the order as shown in FIG. 1A, 2A, 3 or 4. The HPV HTL epitopes can be directly or indirectly linked in the order as shown in FIG. 1B or 2B. [0021] Optionally, the polynucleotide of the present invention further comprises one or more regulatory sequences. Preferably, said regulatory sequence is an internal ribosome binding site (IRES). [0022] In a specific embodiment, the polynucleotide of the present invention further comprises one or more promoters. Preferably, the promoter is a CMV promoter. [0023] In a further embodiment, the polynucleotide of the present invention further comprises one or more signal sequences. Preferably, the signal sequence is a Igkappa signal sequence. [0024] In another embodiment, the polynucleotide of the invention comprises one or more MHC class I and/or MHC class II-targeting sequences. Preferably, the targeting sequence is selected from the group consisting of tissue plasminogen activator signal sequence, insulin signal sequence, endoplasmic reticulum signal sequence, LAMP-1 lysosomal targeting sequence, LAMP-2 lysosomal targeting sequence, HLA-DM lysosomal targeting sequence, HLA-DM-association sequences of HLA-DO, Ig-alpha cytoplasmic domain, Ig-beta cytoplasmic domain, Ii protein, influenza matrix protein, HBV surface antigen, HBV core antigen, and yeast Ty protein. [0025] Ina specific embodiment, the polynucleotide of the present invention comprises a polyepitope construct encoding the amino acid sequence consisting of, comprised in or comprising the sequence represented by SEQ ID NO 123, SEQ ID NO 125, SEQ ID NO 127 or SEQ ID NO 129. In another embodiment the polyepitope construct is characterized by or comprised in the nucleic acid sequence represented by SEQ ID NO 124, SEQIDNO 126, SEQIDNO 128 or SEQ ID NO 130. [0026] In a further embodiment, the polyepitope construct encodes the amino acid sequence consisting of or comprising the sequence represented by SEQ ID NO 156, SEQ ID NO 158, SEQIDNO 160, or SEQ ID NO 162. In another embodiment, polyepitope construct consists of or comprises the nucleic acid sequence represented by SEQ ID NO 157, SEQ ID NO 159, SEQ ID NO 161, or SEQ ID NO 163. [0027] Furthermore, the invention encompasses a vector comprising the polynucleotide as described herein. Preferably, the vector is an expression vector. More preferably, the vector is a plasmid (pdna), a viral, a bacterial or a yeast vector. Ina further embodiment, the viral vector is a pox virus. Preferably, the pox virus is a vaccinia virus. More preferably, the vaccinia virus is MVA. [0028] Moreover, the current invention also relates to an isolated polypeptide encoded by the polynucleotide as described herein. [0029] The current invention also relates to a composition comprising the polynucleotide, the polypeptide, or the vector as described herein, or any combination thereof. [0030] Preferably, the composition further comprises a pharmaceutical acceptable excipient or carrier. In a specific embodiment, the composition is a vaccine. [0031] In another embodiment, the present invention relates to the composition, the polynucleotide, the vector or the polypeptide as described herein, for use as a medicament. [0032] Specifically, the invention includes the use of the composition, the polynucleotide, the vector or the polypeptide for the manufacture of a medicament for treating and/or preventing persistent HPV infection. The invention also encompasses the composition, the polynucleotide, the vector or the polypeptide for use in the treatment and/or prevention of persistent HPV infection. Specifically, the invention is directed to the treatment and/or prevention of HPV-related disease. [0033] Moreover, the present invention includes a cell comprising the polynucleotide, the polypeptide, or the vector as described herein. [0034] In a further embodiment, the invention relates to a method of inducing an immune response against HPV in an individual, comprising administering the polynucleotide, the polypeptide, the vector, the composition, or the cell as described herein, or a combination thereof, to said individual.

21 Specifically, the method is directed to the treatment and/or prevention of HPV infection and/or HPV-related disease. [0035] Furthermore, the invention covers a method of making the polynucleotide, the polypeptide, the vector, the composition, or the cell as described herein. FIGURE LEGENDS [0036] FIG. 1: A. Specific order of CTL epitopes in construct ICCG6150 [0037] B. Specific order of HTL epitopes in construct ICCG6150 or ICCG6149 [0038] FIG. 2: A. Specific order of CTL epitopes in construct ICCG6138 [0039] B. Specific order of HTL epitopes in construct ICCG6138 or ICCG6137 [0040] FIG. 3: Specific order of CTL epitopes in construct ICCG6137 [0041] FIG. 4: Specific order of CTL epitopes in construct ICCG6149 [0042] FIG. 5: Construct ICCG6137 [0043] A. Amino acid sequence of the signal sequence (in italics) and the polyepitope; [0044] B. DNA sequence: The start and stop codons are underlined. The signal sequence is shown in italics, and the epitope-coding sequence is bolded. [0045] C. Amino acid sequence of the polyepitope; [0046] D. DNA sequence of the polyepitope. [0047] FIG. 6: Construct ICCG6138 [0048] A. Amino acid sequence of the signal sequence (in italics) and the polyepitope; [0049] B. DNA sequence: The start and stop codons are underlined. The signal sequence is shown in italics, and the epitope-coding sequence is bolded. [0050] C. Amino acid sequence of the polyepitope; [0051] D. DNA sequence of the polyepitope. [0052] FIG. 7: Construct ICCG6149 [0053] A. Amino acid sequence of the signal sequence (in italics) and the polyepitope; [0054] B. DNA sequence: The start and stop codons are underlined. The signal sequence is shown in italics, and the epitope-coding sequence is bolded. [0055] C. Amino acid sequence of the polyepitope; [0056] D. DNA sequence of the polyepitope. [0057] FIG. 8: Construct ICCG6150 [0058] A. Amino acid sequence of the signal sequence (in italics) and the polyepitope; [0059] B. DNA sequence: The start and stop codons are underlined. The signal sequence is shown in italics, and the epitope-coding sequence is bolded. [0060] C. Amino acid sequence of the polyepitope; [0061] D. DNA sequence of the polyepitope. DETAILED DESCRIPTION OF THE INVENTION [0062] The present invention is directed to a polynucleotide or polypeptide comprising a polyepitope construct encoding or comprising epitopes derived from the El, E2, E4, E5, E6 and/or E7 protein of the Human Papillomavirus (HPV). The epitopes are those which elicit a HLA class I- and/or class II-restricted T-lymphocyte response in an immunized host. More specifically, the present invention describes highly optimized and effective polyepitope constructs characterized by efficient processing and comprising highly immunogenic epitopes allowing efficient treatment of patients at different stages of HPV-related disease. Identification of the Epitopes [0063] CTL binding epitopes were evaluated for their immunogenicity in different HLA transgenic mice. To this, a single immunization with CTL peptide pools together with a common HTL epitope emulsified in IFA was performed and up to 14 days later, CD8+ spleen cells were isolated and evaluated for epitope specificity using a direct ex vivo IFNy ELISPOT assay. The majority of high affinity binding CTL epitopes proved to be immunogenic. HTL binding epitopes were evaluated for their induction of (ex vivo) recall T cell responses using PBMC from HPV patients. To this, PBMC from subjects were cultured in vitro for 1-2 weeks in the presence of test peptide plus antigen-presenting cells (APC to allow activation of "memory" T cells, as compared to "naive" T cells). At the end of the culture period, T cell activity was detected using assays such as s 1Cr release involving peptideloaded target cells, T cell proliferation, or cytokine release. [0064] The CTL epitopes of the present invention are given in Table 1. Each individual epitope is part of the invention as well as combinations of two, more, or all of said epitopes. In a specific aspect of the invention, epitopes have been identified in the E4 and E5 proteins of the high risk HPV genotypes HPV 16, 18, 31 and 45, whereby said epitopes are being characterized by SEQ ID NO 8, 17, 29, 42, 43, 51, 52, 64, 74, 75, 81 and 86. As such, the present invention also relates to a combination comprising 2,3,4,5,6,7,8,9, 10, 11 or all of the epitopes characterized by SEQ ID NO 8, 17, 29, 42, 43, 51, 52, 64, 74, 75, 81 and 86, optionally linked to each other in a polyepitope construct. [0065] Starting from said pool of CTL epitopes, the present inventors were successful in creating a potent, multi-specific and full-spectrum vaccine addressing the different stages of HPV infection, and broadening the treatment window. [0066] The polyepitope construct ofthe present invention is particularly useful to prevent and/or treat HPV infection, more specific HPV-related disease, and even more specific the precancerous stages of HPV infection, i.e. CIN 1-3. HPVrelated disease includes neoplasia and HPV related cancers such as but not limited to cervical cancer and head and neck carcinoma. The neoplasia to be treated with the methods and medicaments according to the current invention may be any HPV induced neoplasia, preferably in an epithelial tissue, in the ano-genital area and/or ano-genital tract, comprising the vulva, vagina, cervix, penis, scrotum, anus and rectum. The neoplastic disorders to be treated comprise Cervial Intraepithelial Neoplasia of various grades (CIN 1, 2 and 3), Vulvar intraepithelial neoplasias of various grades (VIN 1, 2 and 3) and Vaginal intraepithelial neoplasias (VAIN) and anal intraepithelial neoplasia (AIN). Also male subjects suffering from virally induced neoplasias in the ano-genital area and/or tract, such as but not limited to, Penile intraepithelial neoplasia (PIN) and Anal intraepithelial neoplasia (AIN), may be treated according to this invention. Although most HPV infections do not progress to cervical cancer, infections that persist for many years are more likely to do so. Most cervical cancers develop slowly through a series of abnormal changes in the cells of the cervix. Regular Pap tests can detect these changes and the abnormal tissue can be removed, preventing it from ever developing into cancer. Various terms have been

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